Pharmaceutical compositions for demodex related blepharitis and eyelid crusting

ABSTRACT

Formulation of ectoparasiticidal and antibiotic “compositions into pharmaceutical compositions useful for the treatment of eyelid inflammation, in particular demodex related blepharitis and eye crusting.

TECHNICAL FIELD

The present invention relates to the formulation of ectoparasiticidaland antibiotic compositions into topical pharmaceutical compositionsuseful for the treatment of eyelid inflammation, in particular demodexrelated blepharitis and eyelid crusting. This invention also relates toa topical pharmaceutical composition suitable for the treatment ofmammalian ectoparasites.

DESCRIPTION OF BACKGROUND AND/OR RELATED AND/OR PRIOR ART

Blepharitis represents one of the most common anterior segment disordersencountered in ophthalmology. Blepharitis produces a red-rimmedappearance at the margins of the eyelids. It affects both the upper andlower eyelids. Blepharitis tends to recur and can become chronic.

Blepharitis is inflammation usually involving the part of the eyelidwhere the eyelashes grow. The eyes can eventually become red, itchy andirritated, with dandruff-like crusts appearing on the eyelashes (alsoknown as “crusting”). It may also result in loss of lashes.

Recent studies show that ophthalmologists and optometrists observeblepharitis in approximately 37% to 47% of their patients. Despite theprevalence of blepharitis in both presentation and contribution toocular conditions, there is little data on how eye care practitionerstreat the disease.

A number of causes for blepharitis exist, including bacterialinfections, parasitic infestation, viral infection and autoimmuneconditions. Infective causes including bacteria and parasites are likelyto be the most common causes. There are two types of blepharitis, i.e.anterior and posterior blepharitis. Anterior blepharitis is a conditionwhere the outside front edge of the eyelids is inflamed, where theeyelashes are attached. Posterior blepharitis is a condition where themoist inside part of the eyelid is affected.

The traditional treatment for blepharitis consists of lid hygiene, andthe application of a variety of “proprietary” cleansers. The goal is tocontrol the disease and its underlying causes, maintain vision and toavoid secondary complications. However, many chronic cases persist.Demodex mites have been thought to be an etiologic factor in many casesof anterior blepharitis with lid margin debris. Demodex infestations arecommonly treated with systemic and topical administration ofparasiticides. For example, ocular demodex can be treated by performinga daily eyelid margin scrub with diluted shampoo alone or incombinations with a mercury oxide ointment, a metronidazole gel, or apilocarpine gel applied to the base of the eye lashes. However, thesetreatments frequently fail to eradicate the demodex parasite and theinfestation persists.

U.S. Pat. No. 8,128,968 teaches a composition containing about 0.6% toabout 20% of tea tree oil to treat ocular demodex infestations andrelated conditions. Tea tree oil treatments, however, suffer fromseveral disadvantages. Tea tree oil can easily lead to eye irritationand cause stinging sensations. Even a small amount will induce tearing,if it reaches the ocular surface. Due to the reflex tearing, dilutionoccurs and efficacy is reduced. Owing to the possibility of severeirritation, some eye centres carry out clinic based treatments, wherethe tea tree oil is professionally applied by an eye doctor. Tea treeoil compositions for home applications are thinner, which has little orperhaps no effect on the demodex mite population.

U.S. Pat. No. 5,952,372 teaches the use of treating demodex with oraladministration of ivermectin. More specifically, oral ivermectin in aregimen of 200 micrograms per kilogram body weight per dose for 2 or 3consecutive doses are given to the patient, at least 3 and not more than7 days apart. Oral tetracycline was also given to the patients throughconsistent intermediate stages. However, this is an expensive medicationregimen and requires repeated dosing. In our experience, a single dose,as used in some centers, does not eliminate the demodex mites. This islikely due to the pharmacokinetic properties of the ivermectin beingpartitioned into the various body compartments, with low concentrationsat the specific target site.

Alternatively, U.S. Pat. No. 5,952,372 teaches topical ivermetincompounded to a 2% concentration by weight in a cream, lotion, or gelcarrier vehicle as a treatment for all clinical stages and signs ofrosacea in affected persons. However, this is only in relation to usinga single active agent, ivermectin, for the treatment of a generaldermatological condition such as rosacea, rather than specificallytargeting blepharitis.

Demodex mites have also been found to be associated with variousbacteria, including Bacillus oleronius. It is therefore possible thatother bacteria play a role in the pathogenic process. Demodex miteskilled by tea tree oil or via oral administration of ivermectin usuallydisintegrate on the ocular surface and release a variety of associatedorganisms, which probably explains why, in our experience, a proportionof patients continue to suffer the usual symptoms of blepharitis,despite eradication of the demodex mites.

DETAILED DESCRIPTION

The aim of this invention is to overcome blepharitis, by eliminatingdemodex mites and/or other associated bacteria.

The demodex species are microscopic, obligate, elongated mites whichbelong to the family “Demodicidae” of the order Acari of the classArachnida. Demodex folliculorum and demodex brevis are foundparasitizing on the human body surface. Demodex folliculorum occupiesthe hair follicles and upper sebaceous glands, whilst Demodex brevisexists principally in the depth of the sebaceous glands [source: “Ameta-analysis of association between Acne vulgaris and Demodexinfestation” by Ya-e Zhao, Li Hu, Li-Ping Wu, Jun-xian Ma, J ZhejiangUniv Sci B. 2012 March; 13(3):192-202].

This invention contains a parasiticidal agent such as ivermectin, and anantibiotic such as oxytetracycline, or any other tetracycline ormacrolide antibiotic. Other types of antibiotics are also suitable, suchas fluoroquinolones and aminoglycosides. Tetracycline antibioticscomprise a class of anti-microbials with applications in human andveterinary medicine, and are among the most heavily used antibiotics inthe world. The purpose of antibiotics is to kill harmful bacteria, wherepossible, or to at least reduce their proliferation with bacteriostaticcompounds.

The pharmaceutical composition according to the invention are suited fortreating blepharitis and may be in liquid, pasty form, and moreparticularly in the form of creams, ointments, milks, pomades, powders,impregnated pads, syndets, towelettes, solutions, gels, sprays, foams,suspensions, lotions, sticks, shampoos, or washing bases.

In a preferred embodiment of this invention, the pharmaceuticalcomposition according to the invention is in the form of an emulsion ofthe cream. In this embodiment, the compositions according to theinvention are in the form of an emulsion. Most simple emulsions areoil-in-water, which means that the oil droplets are suspended in acontinuous water phase, whereas others are water-in-oil. Emulsions canbe classified as either oil-in-water (O/W) or water-in-oil (W/O)emulsions, depending on whether oil or water is the dispersed phase.Milk, cream and sauces are some examples of oil-in-water emulsions. O/Wemulsion is preferred in this embodiment, where oil molecules aredispersed in water. Water therefore evaporates more readily from O/Wemulsion. There are also more complicated emulsions that are used toenhance the delivery and stability of certain active ingredients. Thechoice of emulsification system is therefore highly dependent on thechoice of ingredients comprised in the cream. Cream, regardless if it iscold cream, emollient cream, day cream, night cream, medicated cream,etc, all have the same basic emulsion formulation. The effectiveness ofthe cream further depends on the emulsion type and pH, as well as thetype of oils, fats, alcohols and esters used.

In the above preferred embodiment of this invention, sorbitol is used asa humectant, so that the cream will not “dry out” when exposed to theatmosphere for prolonged periods of time. It also assists in maintainingphase stability, such as preventing separation of the aqueous andnon-aqueous components.

The other ingredients used in this embodiment of the invention aredetermined by referring to the Cosmetic Ingredient Review (“CIR”), orany other toxicological reports, where available, so as to ensure thatthese chosen ingredients are suitable for topical application and havelower risk of causing ocular irritation. The CIR was established in 1976by the industry trade association (then the Cosmetic, Toiletry, andFragrance Association, now the Personal Care Products Council, locatedin the United States of America), with the support of the U.S. Food andDrug Administration and the Consumer Federation of America. Althoughfunded by the Council, CIR and the review process are independent fromthe Council and the cosmetics industry.

In this embodiment, emulsifying wax is used. There are several varietiesof emulsifying wax available. Some are synthetically produced and someare vegetable-derived. This embodiment uses vegetable-based emulsifyingwax NF (which means that it conforms to the specifications of theNational Formulary, or “NF”), which is from naturally occurring fats andesters, derived from cetostearyl alcohol. Emulsifying wax (NF) is alsosuitable for most skin types as allergic reactions and skinsensitivities have rarely been recorded, in relation to such waxes.

According to the Final Report on the Safety Assessment of Fossil andSynthetic Waxes, International Journal of Toxicology (May/June 1983, 3:43-99), concentrations of the Emulsifying Wax NF in the range of 1%-10%are found in typical use in skin cream. The ocular irritation ofEmulsifying Wax NF was also studied in rabbits (according to the Draizemethod). The “Draize Test” is an acute toxicity test devised in 1944 bythe Food and Drug Administration toxicologists John H. Draize and JacobM. Spines. Initially used for testing cosmetics, the procedure involvesapplying 0.5 mL or 0.5 g of a test substance to the eye or skin of arestrained, conscious animal, and then leaving it for a set amount oftime before rinsing it out and recording its effects. The Draize Testhas since become an endorsed method to evaluate the safety of materialsmeant for use in or around the eyes.

According to the Amended Safety Assessment of Alkyl Esters as Used inCosmetics, Cosmetics Ingredient Review (Apr. 12, 2013), EthylhexylStearate is safe for use and the undiluted test material was at mostmildly irritating to rabbit skin. In a 6-day cumulative skin irritationstudy, an undiluted test material (which had a mean maximum irritationindex (MMII) of 0.67) was poorly tolerated, whereas a 10% aqueoussolution (which had a MMII of 0.33) was relatively well tolerated. Inhuman testing, a formulation containing 7.6% of Ethylhexyl Stearate wasnot an irritant or sensitizer (56 subjects), and not phototoxic (10subjects), and not a photosensitizer (27 subjects), although some slightreactions were reported in the photosensitization study. The undilutedtest material did not provoke any significant injury in the rabbits eyes(max Primary Irritation Index (PII) 4.67/100 at 1 h). The Report statedthat the reproductive toxicity of 2-ethyl-1-hexanol was alreadyaddressed in a fetotoxicity study (performed on diethylhexyl adipate);it was suggested that the fetotoxicity reported for mice in that studywas actually due to a zinc deficiency and that given the extent of2-ethyl-1-hexanol absorption and the load that would be expected toenter the hepatic circulation, the potential for2-ethyl-1-hexanol-induced reproductive toxicity was not thought to be anissue.

According to the report: Safety Assessment of Cyclomethicone,Cyclotetrasiloxane, Cyclopentasiloxane, Cyclohexasiloxane, andCycloheptasiloxane, International Journal of Toxicology (30 (Supplement3)), rats were exposed to up to 700 ppm (0.07%) of Cyclopentasiloxanevia inhalational (environmental) exposure for 5 days per week, for 12months and 24 months respectively, and no eye lesions were found.

In the report: Safely Assessment of Tocopherols and Tocotrienols as Usedin Cosmetics, Cosmetics Ingredient Review (Apr. 4, 2014), it wasreported that tocopheryl acetate was not irritating to rabbit eyes inone study, but it produced weak to moderate conjunctival irritation inanother study (European Chemicals Agency. 3,4-dihydro-2, 5, 7,8-tetramethyl-2-(4, 8, 12-trimethyldecyl)-2H-benzopyran-6-yl acetate).Undiluted tocopheryl acetate was instilled into the conjunctival sac of3 Vienna White rabbits, and the eyes were not rinsed. The eyes werescored at 1, 24, 28, and 72 h after instillation. Slight irritation wasobserved at 1-48 h, and the eyes were normal at 72 h. In a modifiedDraize Test, the same protocol was followed, and undiluteddl-α-tocopherol was instilled into the eyes of six rabbits; again, theeyes were not rinsed. Weak to moderate conjunctival irritation (i.e.,redness) was observed, which subsided by day 7. No corneal changes werereported.

Although mild irritation is shown in the studies by the EuropeanChemical Agency (while some others showed no irritation), thisembodiment of the invention uses diluted tocopheryl acetate.

According to the Final Report on the Safety Assessment of EDTA(Ethylenediaminetetraacetic acid), calcium disodium EDTA, diammoniumEDTA, dipotassium EDTA, disodium EDTA, TEA-EDTA, tetrasodium EDTA,tripotassium EDTA, trisodium EDTA, HEDTA, and trisodium HEDTA,International Journal of Toxicology, (21 (Supplement 2); 95-142, 2002).Disodium EDTA was classified as a non-irritant in a primary mucousmembrane irritation test using rabbit eyes. EDTA of approximately 0.5%to 1% is not toxic when added to balanced salt solutions.

According to the Final Report on the Safety Assessment ofMethylisothiazolinone and Methylchloroisothiazlinone, Journal of theAmerican College of Toxicology (Volume 11, Number 1, 1992),Methylisothiazolinone and Methylchloroisothiazlinone (MI/MCI) wereevaluated for ocular irritation in eight Draize or modified Draize testsusing albino rabbits. MI/MCI-886 ranging in concentration from 1.1% to14% active ingredient (a.i.) and MI/MCI-GC with a 1.5% a.i.concentration were corrosive when tested as supplied. However, aqueousdilutions of MI/MCI-886 with concentrations of 0.056% a.i. werenon-irritating; 0.28% a.i was slight to moderately irritating; 0.56% and1.7% a.i. were moderately to severely irritating; and 2.8% and 5.6% a.i.were severely irritating (corrosive).

As this invention is to be used topically, good absorption is achievedby using Propylene Glycol as a solvent for the ivermectin. According tothe Cosmetic Ingredients Report Panel Meeting on Jun. 28-29, 2010, theocular irritation of Propylene Glycol was determined using groups of 6males and female New Zealand white albino rabbits. Undiluted PropyleneGlycol was found to be a slight eye irritant. In this embodiment,Propylene Glycol is therefore diluted by approximately 10 times, and istherefore non-irritating to the eye, as seen in the our experimentalstudies on the patients.

The selection of the ingredients depends very much on the final purposeand the desired consistency (for example, creamy, hard, soft, greasy, ordry) of the invention. Changing one ingredient may also require changesin many others, if the physical characteristics of the invention are tobe maintained.

Based on the abovementioned reports and scientific researches, variousingredients were selected for this invention.

According to one embodiment of the invention, the compositions comprisethe following range (by weight):

ivermectin (1 to 5%)

an antibiotic such as oxytetracycline, and/or other tetracycline,macrolide, fluoroquinolone, or aminoglycoside antibiotic. (1 to 5%)

water (45 to 65%)

emulsifying wax NF (Cetearyl Alcohol, Polysorbate 60, PEG-150 Stearate,and Steareth-20) (5% to 15%)

ethylhexyl stearate (5% to 15%)

cyclopentasiloxane (0.01% to 0.05%)

sorbitol (1 to 10%)

tocopheryl acetate (0.01% to 0.5%)

disodium EDTA (0.01% to 0.1%)

propylene glycol (3% to 10%)

methylchloroisothiazolinone and methylisothiazolinone (0.001% to 0.01%).

The pharmaceutical composition according to the preferred embodiment isin the emulsion of a cream. In another embodiment, the invention is inthe form of an ointment. A cream is a preparation of a medication fortopical use that contains a water base. Essentially, it is a preparationof oil in water. An ointment is a preparation of a medication fortopical use that contains an oil base, which is essentially apreparation of water in oil.

In another embodiment, the pharmaceutical composition according to theinvention which is in the form of an ointment, which comprise thefollowing range (by weight):—

ivermectin (1-5%)

tetracycline (1-5%)

sorbitan monooleate (span 80) (3-5%)

light mineral oil (10%-15%)

petrolatum (70%-80%)

Whether in the form of a cream or ointment, the pharmaceuticalcomposition according to the invention is therefore formulated in a waythat it does not cause eye irritation, even if a small amount reachesthe ocular surface. This invention therefore allows patients to applysuch medication themselves, without having to go to a clinic. Patientsmay be able to continuously repeat the dosage over a period of time, soas to ensure a lower risk of recurrence of blepharitis.

In this invention, the topical application of the cream or ointmentallows the ivermectin and antibiotic to be applied directly to theaffected area, thus overcoming the problem associated with oralapplication of ivermectin being partitioned into the various bodycompartments, consequently with low concentrations at the specifictarget site. The direct topical application of the cream or ointmentonto the affected area also minimises the risk of medication-relatedside effects felt in other parts of the body.

The cream or ointment is applied to the eyelids, in particular toeyelashes and the base of the eyelashes.

The cream or ointment may also be used to treat other conditions. It wasmentioned in “A meta-analysis of association between acne vulgaris andDemodex infestation”, published in 2012, that there is evidence(Including one meta-analysis) which suggests a connection between acnevulgaris and demodex. There is also other evidence which suggests arelationship between acne rosacea and demodex. For example, an earlierpublication, Severe Demodex folliculorum-associated OculocutaneousRosacea In A Girl Successfully Treated With Ivermectin (JAMA Dermatol2014 January; 150(1):61-3) reported the case of a 12-year old girl whowas successfully treated with oral ivermectin. Other reports includeCorrelation Between Serum Reactivity To Demodex-associated BacillusOleronius Proteins, and Altered Sebum Levels and Demodex Populations inErythematotelangiectatic Rosacea Patients (J Med Microbiol 2014February; 63 (Pt 2): 258-72, Evaluation of Demodex folliculorum As ARisk Factor for the Diagnosis of Rosacea in Skin Biopsies (Indian JDermatol. 2013 March, 58(2):157, Potential Role of Demodex Mites andBacteria in the Induction of Rosacea (J Med Microbiol 2012 November 61(Pt 11): 1504-10), and Correlation Between Ocular Demodex Infestationand Serum Immunoreactivity to Bacillus Proteins in Patients with FacialRosacea (Ophthalmology 2010 May: 117(5): 870-977). Accordingly, thisinvention may be used to treat other medical conditions as well.

The cream or ointment is topically administered every night to theaffected areas, for the treatment of blepharitis and/or acne, to obtainthe appropriate and desired treatment outcome, by using a clean fingeror cotton bud. For example, the invention is to be applied in a lightand gentle rubbing action across the base of the eyelashes by firstclosing the eyes and applying to the upper eyelid eyelash bases/roots,and then looking upwards so that the invention can be applied to thelower eyelid eyelash bases/roots. The invention is left on the affectedarea overnight.

The invention is then removed with normal cleansing water in themorning, for a month, so as to avoid early recurrences from newgenerations of mites which may emerge from unaffected eggs.

EXAMPLES

The following examples are merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever. These examplesare illustrative of the effectiveness of the invention.

Several patients had itching in the eyes and crusting around theeyelids. The presence of demodex mites was then confirmed. Theconfirmation was done by gently pulling on the eyelashes, and thentransferring the presenting demodex mites onto a piece of cellophanetape. The said cellophane tape was then affixed onto a microscope slide.These demodex mites were viewed at 100 times of magnification, andcounted to determine the mite density per lash follicle.

In treating the affected patients, the eyelids were first cleaned withhot compresses and a clean towel to remove all crusts and debris. Thecream or ointment was then applied directly onto the affected area, byusing a clean finger or a cotton-tipped applicator. The cream orointment covered the entire eyelashes and roots.

The cream or ointment was left on the affected area for the entirenight, and then washed away in the morning. This process was repeated ona nightly basis, for a month. The patients were then re-assessed for thepresence of demodex mites, and no demodex mites were found on theeyelash roots of any patients. Before the treatment, many patientsexperienced itching on the eyelid margins. These patients were free ofany symptoms, at the 1-month follow up.

Some cases were treated solely with ivermectin. However, these studiesalso demonstrate the necessity of antibiotics, in some cases.

Example 1

This 52 year old Chinese gentleman had a long history of facial skinrashes that occurred along the nasolabial fold (also commonly known as“smile lines” or “laugh lines”) as well as around the ears. He hadpreviously been treated by dermatologists for a diagnosis of seborrhoeicdermatitis with various creams including topical steroids. He presentedwith increasing crusting around the eyelashes and intermittent eyeirritation. On examination, erythematosus macules and papules were notedalong the glabellar area as well as the nasolabial folds bilaterally.Marked crusting and many demodex mites were found in the eyelashfollicles. A sample retrieved from one eyelash revealed 5 Demodexfolliculorum in the single follicle. He was treated with Ivermectin(only comprising 1%) cream nightly to the eyelid margins (asprescribed), as well as the inflamed areas of his face. One month laterthe eyelid margin crusting had resolved, as had the facial rash. Nodemodex mites were found in the eyelash follicles after the treatment.

Example 2

This 44 year old Caucasian gentleman had recurring redness of the eyesassociated with itching and burning sensations for the past 6 years. Onexamination, eyelash crusting together with lid margin erythema and manydemodex mites were seen. He was first treated with oral Ivermectin(Stromectol) 12 mg and was advised to do scrubs using Tea Tree Oil onthe eyelids twice a day. Over the next 2 months, the demodex mitesreduced in numbers but were not completely eliminated, despite 4subsequent doses of oral Ivermectin and continuing Tea Tree Oil scrubs.Tea Tree Oil applications were also performed on the patient. Owing tothe persistence of the mites, dosages of Ivermectin (1%) cream wasprescribed instead. After nightly applications of this cream for onemonth (as prescribed), no demodex mites were seen in the eyelashfollicles and his ocular inflammation had markedly improved.

Example 3

This 28 year old Chinese gentleman had recurring redness on the lefteyelids for the past 9 years and had been treated previously with avariety of topical antibiotics including Framycetin. On examination, hehad asymmetric disease, with severe inflammation of the left eyelidmargins and corneal punctuate erosions. Some demodex mites were seen inthe eyelash follicles. He was treated with a combination of Ivermectin(1%) cream as well as Tetracycline eye ointment to the eyelids. OralDoxycycline 100 mg twice a day was prescribed. Demodex mites resident inthe lash follicles were eradicated after 1 month of nightly Ivermectincream applications, as prescribed. Although eyelid inflammation wasreduced, it was not entirely eliminated and the topical and oraltetracycline treatment was continued for the next 2 months. 4 monthsafter initial presentation, the eyelids were much improved andinflammation had subsided. He was followed up for 2 years, and duringthis time remained free of severe episodes of eye or eyelidinflammation. A mild recurrence of demodex infestation was noted at thesecond year mark, and this was treated successfully with a furthercourse of Ivermectin (1%) cream.

1. A method for the treatment of eyelid inflammation, in particulardemodex related blepharitis and eyelid crusting, comprising topicallyadministering every night for a month onto the affected area of anindividual in need of such treatment and removed with normal cleansingwater in the morning, a topical pharmaceutical composition whichcomprises an effective amount of ivermectin and an antibiotic, saidtopical pharmaceutical composition being formulated as an emulsion of acream, the topical pharmaceutical cream comprising: water; an humectantcomprising sorbitol; a mixture of emollient comprisingcyclopentasiloxane, ethylhexyl stearate; an emulsifier comprisingemulsifying wax NF; a mixture of preservatives comprisingmethylchloroisothiazolinone, disodium EDTA; an antioxidant comprisingtocopheryl acetate; and a solvent comprising propylene glycol.
 2. Themethod defined by claim 1, wherein said ivermectin is present in therange of 1 to 5% (by weight) of the topical pharmaceutical composition.3. The method defined by claim 1, wherein said antibiotic comprises ofoxytetracycline in the range of 1% to 5% (by weight) of the topicalpharmaceutical composition. 4.-12. (canceled)
 13. The method defined byclaim 1, wherein said antibiotic can also comprise tetracycline.
 14. Themethod defined by claim 1, wherein said antibiotic can also comprise amacrolide antibiotic.
 15. The method defined by claim 1, wherein saidantibiotic can also comprise fluoroquinolones.
 16. The method defined byclaim 1, wherein said antibiotic can also comprise aminoglycosides.17.-22. (canceled)
 23. A topically applicable stable pharmaceuticalemulsion of cream, comprising: — ivermectin an antibiotic; water; anhumectant comprising sorbitol; a mixture of emollient comprisingcyclopentasiloxane, ethylhexyl stearate, an emulsifier comprisingemulsifying wax NF; a mixture of preservatives comprisingmethylchloroisothiazolinone, disodium EDTA; an antioxidant comprisingtocopheryl acetate; and a solvent comprising propylene glycol.
 24. Thetopically applicable stable pharmaceutical emulsion of cream as definedby claim 23, wherein said ivermectin is present in the range of 1% to 5%(by weight) of the topical pharmaceutical composition.
 25. The topicallyapplicable stable pharmaceutical emulsion of cream as defined by claim23, wherein said antibiotic is present in the range of 1% to 5% (byweight) of the topical pharmaceutical composition. 26.-34. (canceled)35. The topically applicable stable pharmaceutical emulsion of cream asdefined by claim 23, wherein said antibiotic can also comprisetetracycline.
 36. The topically applicable stable pharmaceuticalemulsion of cream as defined by claim 23, wherein said antibiotic canalso comprise macrolide antibiotic.
 37. The topically applicable stablepharmaceutical emulsion of cream as defined by claim 23, wherein saidantibiotic can also comprise fluoroquinolones.
 38. The topicallyapplicable stable pharmaceutical emulsion of cream as defined by claim23, wherein said antibiotic can also comprise aminoglycosides.
 39. Atopically applicable stable pharmaceutical in the form of an ointment,comprising: — ivermectin; an antibiotic; a solvent comprising sorbitanmonooleate (span 80); and a mixture of ointment base comprising lightmineral oil, petrolatum.
 40. The topically applicable stablepharmaceutical in the form of an ointment as defined by claim 39 whereinsaid ivermectin is present in the range of 1% to 5% (by weight) of thetopical pharmaceutical composition.
 41. The topically applicable stablepharmaceutical in the form of an ointment as defined by claim 39 whereinsaid antibiotic is present in the range of 1% to 5% (by weight) of thetopical pharmaceutical composition.
 42. The topically applicable stablepharmaceutical in the form of an ointment as defined by claim 39 whereinsaid sorbitan monooleate is present in the range of 3% to 5% (by weight)of the topical pharmaceutical composition.
 43. The topically applicablestable pharmaceutical in the form of an ointment as defined by claim 39wherein said light mineral oil is present in the range of 10% to 15% (byweight) of the topical pharmaceutical composition.
 44. The topicallyapplicable stable pharmaceutical in the form of an ointment as definedby claim 39 wherein said petrolatum is present in the range of 70% to80% (by weight) of the topical pharmaceutical composition. 45.-48.(canceled)